Gonadotropins are the primary support for Leydig and Sertoli cell function and the most prominent local regulatory hormone of testicular function is testosterone, which is synthesized by the Leydig cells and acts as the major paracrine stimulator of germ cell development. Many additional local regulatory substances act as autocrine modulators and mediate paracrine interactions between the different intratesticular compartments. These include growth factors, several neuropeptides such as GnRH and most importantly, corticotropin releasing hormone (CRF) and opioids, and amines such as serotonin. Corticotropin-releasing hormone factor, the key neuropeptide in the stress cascade, has major inhibitory actions on testicular function in addition to its known antireproductive effects at the central level (inhibition of sexual behavior and LH secretion). Leydig cells in culture are able to produce hypothalamic releasing hormones such as CRF, which acts through distinct high- affinity receptors as a negative autocrine regulator of Leydig cell function by inhibiting gonadotropin-stimulated cAMP generation and steroidogenesis. The secretion of CRF by the Leydig cell is stimulated by LH, acting via release of serotonin (5HT) and autocrine activation of 5HT2 receptors distinct from brain sites (DOI, an agonist for 5HT2 sites in the brain, acts as an antagonist of the high-affinity sites and an agonist to the low-affinity sit in the Leydig cell). Propranolol, the prototype beta-adrenergic blocker frequently used in the control of blood pressure in patients with hypertension, and often associated with impotence, acts in the Leydig cell via serotonergic mechanism to stimulate CRF secretion and causes marked inhibition of LH-induced cAMP production and steroidogenesis. Propranolol, acting as an antagonist of the Leydig cell low-affinity receptor sites (with properties of autoreceptors), promotes the release of serotonin which in turn acts through high-affinity sites to stimulate CRF release. This serotonergic action of the drug could contribute to the impairment of sexual function reported during propranolol treatment. Other studies revealed that another neuropeptide hormone, growth hormone releasing hormone (GHRH), is present in the Leydig cell. The peptide is actively released from cells in culture, is under gonadotropin control, and acts via a VIP receptor as a direct stimulator of Leydig cell function/or facilitator of LH-induced cAMP production and steroidogenesis. Since GHRH is also a stimulus of basal and FSH-stimulated Sertoli cell function, it is concluded that testicular GHRH is an autocrine/paracrine positive regulator of male gonadal function. Altered secretion and actions of testicular GHRH may be involved in certain disorders of androgen production and some forms of male idiopathic infertility.